Created 6/8/2017 Dr. Matthew Fay: Westcliffe Medical Group
Importance of VTE and Superficial Thrombosis for Primary and Emergency
Care
Dr Matthew FayGP Principal The Willows Medical Practice- Queensbury
GPwSI and Co-Founder Westcliffe Cardiology ServiceGP Partner Westcliffe Medical Group
Declaration of interests
• The practice has received funding from: Abbott, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Dawn4S, INRStar,Irhythm, Medtronic, Oberoi Consulting, Pfizer, Qardio, Roche, Sanofi-Aventis, Servier.
• Advisor to:, Anticoagulation Europe, Arrhythmia Alliance, Heart Valve Voice, National Stroke Association, Syncope Trust
• Trustee of Thrombosis UK, AF Association
• Three sections– Recognition and Diagnosis of DVT– Recognition, diagnosis and treatment SVT– Recognition and Diagnosis of PE
Deep Vein Thrombosis• DVT is the formation of a blood clot in a deep
vein.• Usually in the legs; partially or completely
obstructs blood flow.• Annual incidence is about 1 in 1000 people.• The most serious complication is pulmonary
embolism.• Only about a third of people with a clinical
suspicion of DVT have the condition.
Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.
• Risk factors include:– Previous venous thromboembolism.– Cancer (known or undiagnosed).– Increasing age.– Being overweight or obese.– Male sex.– Heart failure.– Acquired or familial thrombophilia.– Chronic low-grade injury to the vascular wall (for
example vasculitis, hypoxia from venous stasis, or chemotherapy).
Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Deep Vein Thrombosis
• Risk factors that temporarily raise the likelihood of DVT:– Immobility, significant trauma, or direct trauma
to a vein.– Hormone treatment (for example oestrogen-
containing contraception or hormone replacement therapy).
– Pregnancy and the postpartum period.– Dehydration.
Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Deep Vein Thrombosis
• Differential Diagnosis– Physical trauma:
• Calf muscle tear or strain.• Haematoma • Sprain or rupture of the Achilles tendon.• Fracture.
– Cardiovascular disorders:• Superficial Venous Thrombosis• Post-thrombotic syndrome• Venous obstruction or insufficiency, or external compression of major veins• Arteriovenous fistula and congenital vascular abnormalities• Acute limb ischaemia• Vasculitis
– Other conditions including:• Ruptured Baker's cyst• Cellulitis (commonly mistaken as DVT)• Other causes of oedema:-Dependent oedema, Heart failure, Cirrhosis. Nephrotic syndrome.• Lymphatic obstruction.• Septic arthritis.• Compartment syndrome.
Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Deep Vein Thrombosis
• Suspect a DVT if the person has:
– Signs or symptoms of a DVT:• Pain and swelling in one leg, although both legs
may be affected.• Tenderness, changes to skin colour and
temperature, and vein distension.– A risk factor for DVT
• previous VTE• Immobility
• To exclude an alternative cause:– Carry out a physical examination.– Review the person's general medical history.
Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Deep Vein Thrombosis
Managing a suspected DVT • Refer immediately if pregnant or given birth
within the past 6 weeks.– Requires same-day assessment and management as it is not possible to
accurately assess the risk of DVT in primary care.
• For everyone else, use the two-level DVT Wells score to assess likelihood of DVT and inform further management.
Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Deep Vein Thrombosis
Using the two-level DVT Wells score
Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Criteria Score
Active cancer (treatment ongoing, within the last 6 months, or palliative). 1
Paralysis, paresis, or recent plaster immobilization of the legs 1
Recently bedridden for 3 days or more, or major surgery within the last 12 weeks requiring general or local anaesthetics
1
Localized tenderness along the distribution of the deep venous system (such as the back of the calf)
1
Entire leg is swollen. 1
Calf swelling by more than 3 cm compared with the asymptomatic leg (measured 10 cm below the tibial tuberosity).
1
Pitting oedema (greater than on the asymptomatic leg) 1
Collateral superficial veins (non-varicose). 1
Previously documented DVT 1
If an alternative cause is considered more likely than DVT. -2
Two-level DVT Wells score• Validated, simple scoring system that
takes into account previous DVT.
oDVT is likely if the score is two points or more.
oDVT is unlikely if the score is one point or less.
Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Deep Vein Thrombosis
Other methods of assessment• Do not use:
– Individual symptoms and signs on their own.• On their own they are poor predictors of the
presence or absence of DVT.– A positive Homans' sign (pain in the calf or
popliteal region on passive, abrupt, forceful dorsiflexion of the ankle with the knee in a flexed position):
• Is insensitive and nonspecific. • Can be painful, and there is a theoretical possibility
of dislodging a thrombus.
Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Deep Vein Thrombosis
If DVT likely (>2 points)• Refer for a proximal leg vein ultrasound scan to
be carried out within 4 hours.• If a proximal leg vein ultrasound scan cannot be
carried out within 4 hours of being requested:– Take a blood sample for D-dimer testing.– Give an interim 24-hour dose of a anticoagulant
• Ensure a proximal leg vein ultrasound scan is carried out within 24 hours of being requested.
Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Deep Vein Thrombosis
Which anticoagulant?• Offer a choice of low molecular weight heparin (LMWH)
– Licensed LMWHs for DVT treatment include dalteparin, enoxaparin, and tinzaparin.
• Offer a choice of Xa Inhibitor– Apixaban and Rivaroxaban– Fondaparinux is a synthetic pentasaccharide that inhibits
activated factor X but is parentral• Choice of anticoagulant depends on:
– Comorbidities– Contraindications– Cost
• Local policy may also influence choice.
Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Deep Vein Thrombosis
If DVT unlikely (< 1point)• Offer D-dimer testing.• If negative D-dimer test - consider an alternative
diagnosis to explain symptoms.• If positive D-dimer test - refer for a proximal leg vein
ultrasound scan to be carried out within 4 hours. • If a proximal leg vein ultrasound scan cannot be carried
out within 4 hours of being requested:– Give an interim 24-hour dose anticoagulant
• Ensure a proximal leg vein ultrasound scan is carried out within 24 hours of being requested.
Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Deep Vein Thrombosis
Compressive USDeep Vein Thrombosis
US Positive for DVT
Compression
Deep Vein Thrombosis
Three point compression
Above knee only
Deep Vein Thrombosis
What about Serial US?
• No US required if – Low risk and Negative D Dimer
• One US will do if– Negative US and Negative D Dimer - <1% DVT– Negative US and Low risk - <1% DVT
• Two US required if– High risk and Positive D Dimer
Deep Vein Thrombosis
Serial USInfluence of Wells’ score AND Ddimer on need to repeat US
High risk, positive D-dimer, initial negative CU, 9.75% had DVT on repeat CU at one week. Ruis-Gimenez 2004
Deep Vein Thrombosis
Superficial Venous Thrombosis
Superficial Venous ThrombosisRisk factors: Varicose veins Immobilization Trauma Surgery Pregnancy and post-partum Hormonal contraception or replacement therapy Increasing age Obesity History of VTE Malignancy Autoimmune disease Thrombophilia IV catheter
Superficial Venous Thrombosis
Clinical Presentation• Female (55-70% all presentations)• Varicose Veins • Traumatic• Septic and Suppurative• Migratory• Short saphenous• Upper extremity• Post endovascular vein treatment
Superficial Venous Thrombosis
Consequence • A prospective study of 844 patients with SVT >5cm
– 4% symptomatic PE– 10% proximal DVT– 13% distal DVT
• Without VTE at presentation, despite 90% treated– 3.1% developed symptomatic DVT– 1.9% had recurrent DVT– 3.3% had extension of the DVT in the same location
Superficial Venous Thrombosis
Diagnosis• Compression USS
CALISTO study , guidelines recommend 2.5 mg fondaparinux for 45 days
Decousus H, Prandoni P, Mismetti P, et al. Fondaparinux for the treatment of superficial-vein thrombosis in the legs. N Engl J Med. 2010;363(13):1222-32.
Superficial Venous Thrombosis
Comparison of Arixtra in Lower Limb Superficial Vein Thrombosis
(CALISTO) Trial• Randomized , double blind, placeb0-controlled trial
of 3002 patients with SVT > 5 cm in length• Treatments for 45 days of either
- fondaparinux 2.5mg daily (1502 patients)or
- placebo (1500 patients)• Primary outcome: death, symptomatic PE,
symptomatic DVT, or symptomatic extension, symptomatic recurrence
Baseline Characteristics
N Engl J Med. 2010;363(13):1222-32
Superficial Venous Thrombosis
ResultsFondaparinux 2.5mg per day x 45 days• 5% absolute risk reduction• 85% reduction of symptomatic
thromboembolic complications or death• Statistically and clinically significant reductions
in risk of primary efficacy outcome (death, symptomatic PE, symptomatic DVT, symptomatic extension, or symptomatic recurrence)
N Engl J Med. 2010;363(13):1222-32
Superficial Venous Thrombosis
ResultsPlaceboThrombotic complications occurred more often if • SVT involved the long saphenous vein (92%
patients in control group)• Extended to within 10 cm from the
saphenofemoral junction (9% of patients)• Involved veins above the knee (46% of patients) • If VTE (7% of patients) or SVT (12% of patients)
had occurred previously.N Engl J Med. 2010;363(13):1222-32
Superficial Venous Thrombosis
ResultsNumber need to treat (NNT) to prevent one
primary efficacy outcome. NNT = 20Recall primary outcome: death symptomatic PE, symptomatic DVT, symptomatic extension, or symptomatic recurrence
NNT = 80, to prevent DVT or PE
N Engl J Med. 2010;363(13):1222-32
Superficial Venous Thrombosis
Superficial Venous Thrombosis
Superficial Venous Thrombosis
Superficial Venous Thrombosis
Summary• LMWH or NSAID effective for reducing pain and
extension/VTE but risk stratification model not available
• Goals of treatment met by LMWH but dose and duration of LMWH not clear
• ACCP 2012 recommendation (no change 2017):– Superficial thrombosis ≥ 5 cm in length should receive
prophylactic dose fondaparinux or LMWH for 45 days (2B).– Fondaparinux 2.5 mg is preferred over LMWH (2C).
• No UK national guidance on treatment of SVT
Pulmonary Embolism
• A PE is where one or more emboli are lodged in and obstruct the pulmonary arterial system.
• The annual incidence of PE is around 3–4 per 10,000 people.
• A PE may be:
– Provoked – associated with a transient risk factor (e.g. significant immobility, surgery).
– Unprovoked – no identifiable risk factor or a risk factor that is persistent and not easily correctable (e.g. active cancer).
Based on the CKS topic Pulmonary embolism (June 2013), and NICE guidance (2012a): Venous thromboembolic disease: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Pulmonary Embolism
Sources of emboli• The most common source is deep vein thrombosis (DVT) in the
lower limbs (80%).• Other sources include:
o Emboli originating in the abdominal or axillary veins, or from the right ventricle.
o Tumours – mostly prostate and breast cancer. o Fat from long bone fractures.o Amniotic fluid – pregnant women. o Sepsis – e.g. infected indwelling catheters.o Foreign bodies (e.g. during IV drug use).o Air – admitted during surgery.
Based on the CKS topic Pulmonary embolism (June 2013), and NICE guidance (2012a): Venous thromboembolic disease: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Pulmonary Embolism
• Major risk factors include:– Deep vein thrombosis (DVT).– Previous DVT or pulmonary embolism.– Active cancer.– Recent surgery, hospitalization, lower limb
trauma, or other immobilization (including long-distance sedentary travel).
– Pregnancy, in particular 6 weeks postpartum.
Based on the CKS topic Pulmonary embolism (June 2013), and NICE guidance (2012a): Venous thromboembolic disease: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Pulmonary Embolism
• Other risk factors include:– Increasing age (older than 60 years of age).– Combined oral contraception and hormone
replacement therapy.– Obesity (body mass index greater than 30 kg/m2).– One or more significant medical comorbidities (e.g.
heart disease, acute infectious disease, inflammatory conditions).
– Varicose veins.– Superficial venous thrombosis.– Known thrombophilias.
Based on the CKS topic Pulmonary embolism (June 2013), and NICE guidance (2012a): Venous thromboembolic disease: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Pulmonary Embolism
• Other conditions that could mimic the symptoms of a PE include:– Respiratory conditions (e.g. pneumothorax).– Cardiac conditions (e.g. acute coronary syndrome).– Musculoskeletal chest pain.– Gastro-oesophageal reflux disease.– Pregnancy.– Any cause for collapse such as vasovagal syncope.
Based on the CKS topic Pulmonary embolism (June 2013), and NICE guidance (2012a): Venous thromboembolic disease: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Pulmonary Embolism
Complications• Mortality
– Untreated, the risk of death from a PE is high (23–87%). – When treated with heparin and anticoagulants the risk of death
ranges from 2-6%.– For a clinically massive PE the risk of death is about 50%.– PE is the leading cause of maternal deaths in the UK.
• Chronic thromboembolic pulmonary hypertension (CTEPH) – Occurs in 0.5–5% of people with treated PE.
Based on the CKS topic Pulmonary embolism (June 2013), and NICE guidance (2012a): Venous thromboembolic disease: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Pulmonary Embolism
• Suspect a PE if the person has:• Dyspnoea, tachypnoea, pleuritic chest pain, or
features of a DVT.• These features are present in 97% of people with
PE, but• Only 15% of people with a PE have signs of DVT.
• Other features such as tachycardia, haemoptysis, syncope, hypotension (systolic BP less than 90 mmHg), crepitations, cough or fever.
• A risk factor for PE (e.g. previous DVT/PE, pregnant).
Based on the CKS topic Pulmonary embolism (June 2013), and NICE guidance (2012a): Venous thromboembolic disease: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Pulmonary Embolism
• To exclude an alternative cause:– Carry out a physical examination.– Review the person's general medical history.
• ECG or chest X-ray– Are of limited value as they are usually normal
in someone with a PE.– May be done as part of investigations for
breathlessness or chest pain when another diagnosis seems more likely.
Based on the CKS topic Pulmonary embolism (June 2013), and NICE guidance (2012a): Venous thromboembolic disease: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Pulmonary Embolism
• Arrange immediate admission if the person is:– Pregnant or has given birth within the past 6
weeks.• It is not possible to accurately assess the risk of PE in
primary care.– Severely ill with:
• Altered level of consciousness.• Systolic BP of less than 90 mm Hg.• Heart rate of more than 130 beats per minute.• Respiratory rate of more than 25 breaths per minute.• Oxygen saturation of less than 91%.• Temperature of less than 35°C.
Based on the CKS topic Pulmonary embolism (June 2013), and NICE guidance (2012a): Venous thromboembolic disease: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Pulmonary Embolism
Managing a suspected PE• For all other people use the two-level PE Wells
score to assess likelihood of PE and inform further management.
• Using this score a PE is:– Likely if the score is more than 4 points.– Unlikely if the score is 4 points or less.
Pulmonary Embolism
Using the two-level PE Wells score
Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Criteria Score
Active cancer (treatment ongoing, within the last 6 months, or palliative). 1
Heamoptysis 1
Recently bedridden for 3 days or more 1.5
Surgery within the previous 4 weeks 1.5
Heart Rate of greater than 100bpm 1.5
Previous DVT or PE. 1.5
There are clinical features of a DVT 3
If an alternative diagnosis is considered less likely than PE. 3
If PE likely (>4 points)• Arrange immediate admission for a computed
tomography pulmonary angiogram (CTPA), or• If there will be a delay in the person receiving
a CTPA:o Give immediate interim low molecular weight heparin
(LMWH) or fondaparinux, or oral Xa inhibitoro Arrange hospital admission.
Based on the CKS topic Pulmonary embolism (June 2013), and NICE guidance (2012a): Venous thromboembolic disease: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Pulmonary Embolism
If PE unlikely (4 points or less)• Arrange a D-dimer test.• If the D-dimer test is positive:
o Arrange admission to hospital for an immediate CTPA, or
o If a CTPA cannot be carried out immediately, give LMWH, fondaparinux or oral Xa inhibitor and arrange hospital admission.
• If the D-dimer test is negative, consider an alternative diagnosis.
Based on the CKS topic Pulmonary embolism (June 2013), and NICE guidance (2012a): Venous thromboembolic disease: the management of venous thromboembolic diseases and the role of thrombophilia testing.
Pulmonary Embolism
ECG
• ECG may be normal• ECG may reveal tachycardia• Right Heart Strain
– Deep S wave in lead I– Deep Q wave in Lead III– Inverted T wave in Lead III– Right Bundle Branch Block
ECG
Perfusion and ventilation scans
In a patient with pulmonary embolism, a perfusion scan shows that an embolus has stopped the blood flow to part of one lung.
The ventilation scan shows that this area is ventilated normally.
V/Q Scan
CT Angiogram
• Quickly becoming the test of choice for initial evaluation
of a suspected PE.
• CT unlikely to miss any lesion.
• CT has better sensitivity, specificity and can be used
directly to screen for PE.
• CT can be used to follow up “non diagnostic V/Q scans.
Created 6/8/2017 Dr. Matthew Fay: Westcliffe Medical Group
Treatment DVT and PE
Why Treat?
• Prevent DVT becoming PE• Allow fibrinolysis and recanalization.• Prevent recurrent PE• Prevent death• Prevent Re-occurance• Prevent Post Thrombotic Syndrome
Created 6/8/2017 Dr. Matthew Fay: Westcliffe Medical Group
Pharmacological interventions
•Confirmed PE or proximal DVT – offer low molecular weight heparin (LMWH) or fondaparinux as soon as possible, unless:•severe renal impairment•increased risk of bleeding•haemodynamically unstable
•Confirmed PE or proximal DVT and active cancer: offer LMWH, continue for 6 months
Created 6/8/2017 Dr. Matthew Fay: Westcliffe Medical Group
Unfractionated heparin
Created 6/8/2017 Dr. Matthew Fay: Westcliffe Medical Group
Low molecular weight heparin
Created 6/8/2017 Dr. Matthew Fay: Westcliffe Medical Group
Fixed-dose LMWH was as effective and showed a similar safety profile to UFH (i.v. and aPTT controlled) for VTE
treatment
COLUMBUS: incidence of recurrent VTE at 12 weeks
LMWH/VKA(n=510)
UFH/VKA(n=511)
5.3%4.9%
Patie
nts
(%)
Equivalence criteria met
• Rates of major bleeding: 3.1% LMWH versus 2.3% UFH
The Columbus Investigators. N Engl J Med 1997;337:657–662
LMWH versus UFH: data from a meta-analysis
• In a Cochrane meta-analysis of 23 studies, fixed-dose subcutaneous LMWH was more effective and showed a better safety profile than dose-adjusted UFH for the initial treatment of VTE
0
1
2
3
4
5
6
7
Recurrent VTE Major bleeding Overall mortality
LMWHUFH
Inci
denc
e ra
te (%
)
3.6%
5.3%
1.1%
1.9%
4.3%
5.8%
OR=0.7095% CI 0.57–0.85
OR=0.5895% CI 0.40–0.83
OR=0.7795% CI 0.63–0.93
Erkens PM, Prins MH. Cochrane Database Syst Rev 2010;9:CD001100
Problems with LMWH use
• Subcutaneous injection• Injection site problems• Risk of osteoporosis (although less than with
UFH)• A lower risk of HIT compared with UFH• Risk of accumulation with renal impairment
1. Hirsh J et al Blood 1992;79 1-17
Oral anticoagulants
Vitamin K antagonists
VKAs: optimization of initial anticoagulation
• Early studies showed that initial treatment with VKA plus heparin (started together) was more effective than VKA alone1
Inci
denc
e (%
)
20%
6.7%
39.6%
8.2%
60
50
40
30
20
10
0
20%
Symptomatic extension or
recurrence of VTE
Asymptomatic extension of thrombosis
6.7%
39.6%
8.2%
VKA aloneVKA + heparin
1. Brandjes DP et al. N Eng J Med 1992;327:1485–1489
Duration of VKA therapy• The optimal treatment duration should be
based on the underlying risk factors of VTE recurrence and the benefit–risk of long-term anticoagulant therapy
Bleeding
Reduction of VTE
recurrence
Study/sub-group Favours prolonged treatment
Favours shorter treatment
Levine 1995Schulman 1995Schulman 1997Kearon 1999Agnelli 2001Pinede 2001Agnelli 2003Kearon 2004Total
VTE recurrence with continued versus shorter VKA treatment
• Meta-analysis of eight studies of 2,994 patients: consistent reduction in VTE recurrence with prolonged versus shorter treatment (OR=0.18; 95% CI 0.13–0.26)
0.01 0.1 1 10 100
Peto OR and 95% CIs
Hutten B, Prins M. Cochrane Database Syst Rev 2006;1:CD001367
• Meta-analysis of four studies (N=808)*: significant increase in major bleeding with prolonged versus shorter VKA treatment (OR=4.87; 95% CI 1.31–18.15)
Study/sub-group Favours prolonged treatment
Favours shorter treatment
Levine 1995
Kearon 1999
Agnelli 2001
Total
Incidence of major bleeding with continued versus shorter VKA
treatment
0.001 0.01 0.1 1 10 100 1000Peto OR and 95% CIs
*Kearon 2004 not presented (no major bleeding events)Hutten B, Prins M. Cochrane Database Syst Rev 2006;1:CD001367
Outcomes with prolonged VKA therapy
• Prolonged VKA treatment showed consistent reduction in VTE recurrence compared with shorter treatment1
• Major bleeding was increased with prolonged VKA therapy versus shorter treatment1
1. Hutten B, Prins M. Cochrane Database Syst Rev 2006;1:CD001367
Duration of VKA therapy and VTE recurrence
• Prolonged therapy is associated with a lower rate of VTE recurrence
• No significant difference in mortality or in the incidence of major bleeding1
1. Schulman S et al. N Eng J Med 1995;332:1661–1665
2422201816141210864200
0.1
0.2
Months
6-week group
6-month group
Cum
ulat
ive
prob
abili
ty
of V
TE re
curr
ence
(%)
DURAC 11
Endpoint 6 weeks (n=443)n (%)
6 months (n=454)n (%) OR (95% CI), pvalue
Major bleeding 1 (0.2) 5 (1.1) 0.2 (0.0–1.7), 0.23Death 22 (5.0) 17 (3.7) 1.3 (0.7–2.6), 0.46
Duration of VKA therapy and VTE recurrence
• Indefinite VKA therapy after a second episode of VTE was associated with a much lower rate of recurrence – 4 years follow-up1
• Trend towards higher rates of major bleeding with indefinite VKA therapy1
DURAC 21
1. Schulman S et al. N Engl J Med 1997;336:393–398
48423630241812600
20
30
Months
Cum
ulat
ive
prob
abili
ty
of V
TE re
curr
ence
(%)
6-month group
10Indefinite group
Endpoint6 months (n=111)n (%)
Indefinite (n=116)n (%)
RR (95% CI), pvalue ARR (%)
Major bleeding 3 (2.7) 10 (8.6) 0.3 (0.1–1.1), 0.084 -5.9Recurrence 23 (20.7) 3 (2.6) 8.0 (2.5–25.9), <0.001 18.1Death 16 (14.4) 10 (8.6) 1.7 (0.8–3.5), 0.21 5.8
Side-effects associated with VKA use
• Skin necrosis affects <0.1% of patients receiving VKA therapy1
• An increased risk of osteoporosis in elderly patients with atrial fibrillation was noted in men but not in women in a retrospective cohort study2
• Reports of alopecia and birth defects have not been supported– Surveys of dermatology practices suggest alopecia is
uncommon3
– Data collected by institutes collaborating in the European Network of Teratology Information Services (ENTIS) between 1988 and 2004 suggest risk of coumarinembryopathy is very small4
1. Khalid K. J Postgrad Med 2004;50:268–269; 2. Gage BF et al. Arch Intern Med 2006;166:241–246; 3. Umlas J, Harken DE. Cutis. 1988;42:63–64; 4. Schaefer C et al. Thromb Haemost 2006;95:949–957
What’s so wrong with warfarin?• Pros
– Huge clinical experience– Highly effective
• VTE treatment and secondary prevention; stroke prevention in AF; thromboembolic complications with artificial valves
– Predictably reversible (Vit K; PCCs e.g. Beriplex)
• Cons– Prolonged effect– Drug interactions– Food interactions including alcohol– Pharmacokinetics unpredictable
• Requires regular INR monitoring
Limitations with VKAs
• Narrow therapeutic window– Difficult to keep within
therapeutic range1
• Variability in dose response1
• Slow onset/offset of action2
• Frequent INR monitoring/dose-adjustment1
• Multiple drug–drug and food–drug interactions1
• Increased risk of bleeding –when outside of the therapeutic range/window1
Warfarin thrombosisWarfarin bleeding
DoseTh
rom
bosi
s
Blee
ding
Narrow therapeutic
window
1. Ansell J et al. Chest 2004;126:204S–233S 2. Spyropoulos AC. Expert Opin Investig Drugs 2007;16:431–440
Time in therapeutic range (TTR) matters
0 500 1000 1500 2000
Survival to stroke (days)
0.6
0.7
0.8
0.9
1.0
Cum
ulat
ive
surv
ival
71–100%
Warfarin group
61–70%51–60%41–50%31–40%<30%Non warfarin
Morgan CL et al. Thrombosis Research 2009;124:37–41.
Newer Alternatives
Other therapeutic options
Created 6/8/2017 Dr. Matthew Fay: Westcliffe Medical Group
Phase III studies for VTE treatment Trial name Design
Initial treatment with LMWH/
fondaparinux
Treatment duration (months)
Long-term treatment regimen
Active comparator
RivaroxabanEINSTEIN DVT1 Open label No 3, 6 or 12 od LMWH/VKAEINSTEIN PE2 Open label No 3, 6 or 12 od LMWH/VKAEINSTEIN EXT1 Double blind No 6 or 12 od PlaceboDabigatranRE-COVER3 Double blind Yes* 6 bid WarfarinRE-COVER II4 Double blind Yes 6 bid WarfarinRE-MEDY5 Double blind No 18 bid WarfarinRE-SONATE6 Double blind No 6 bid PlaceboApixabanAMPLIFY7 Double blind No 6 bid LMWH/warfarinAMPLIFY-EXT8 Double blind No 12 bid PlaceboEdoxabanHokusai-VTE9 Double blind Yes 12 od# Heparin/warfarin
*Median=9 days; #two 30 mg tablets1. The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510; 2. .EINSTEIN PE. Available at: http://clinicaltrials.gov. Trial ID: NCT00439777. 3. Schulman S et al. N Engl J Med 2009;361:2342–2352 4. RE-COVER II. Available at http://clinicaltrials.gov. Trial ID: NCT00680186. 5. RE-MEDY. Available at: http://clinicaltrials.gov. Trial ID: NCT00329238 6. RE-SONATE. Available at: http://clinicaltrials.gov. Trial ID: NCT00558259 7. AMPLIFY. Available at: http://clinicaltrials.gov. Trial ID: NCT00643201. 8. AMPLIFY-EXT. Available at: http://clinicaltrials.gov. Trial ID: NCT00633893; 9. Hokusai-VTE. Available at: http://clinicaltrials.gov. Trial ID: NCT00986154. All Accessed August 2011
Apixaban 10 mg bid for 7 days, then 5 mg bid for 6 months
R
Apixaban: AMPLIFY
• Primary efficacy outcome: VTE recurrence or death during study treatment• Secondary outcome: bleeding during study treatment
Enoxaparin 1 mg/kg bid until INR ≥2.0, and warfarin adjusted to INR 2.0–3.0 od for 6 months
Day 1
Estimated
N=4,816
Treatment period of 6 months
SymptomaticDVT or PE
Standard therapy
Apixaban
Apixaban placebo 10 mg bid for 7 days,then 5 mg bid for 6 months
Enoxaparin placebo 1 mg/kg bid until sham INR ≥2.0, and warfarin placebo dosing to target sham INR 2.0–3.0 od for 6 months
AMPLIFY. Available at: http://clinicaltrials.gov. Trial ID: NCT00643201. Accessed August 2011
Apixaban: AMPLIFY-EXT
• Primary efficacy outcome: VTE recurrence or death during study treatment• Secondary outcome: bleeding during study treatment
Day 1
Estimated N=2,430
Prevention of VTE recurrence or death in patients who have
completed their intended treatment
for DVT or PEPlacebo
Apixaban 2.5 mg bid for 12 months
Apixaban placebo bid for 12 months
Apixaban
Apixaban 5 mg bid for 12 months
Treatment period of 12 months
R
AMPLIFY-EXT. Available at: http://clinicaltrials.gov. Trial ID: NCT00633893. Accessed August 2011
Rivaroxaban EINSTEIN phase III: study designs
15 mg bid
Confirmed acute symptomatic DVT
without symptomatic PE N=3,449
Rivaroxaban
Day 1 Day 21
Enoxaparin 1.0 mg/kg bid for at least 5 days, followed
by VKA to start ≤48 hours, target INR range 2.0–3.0Confirmed acute symptomatic PE with or without
symptomatic DVT
EINSTEIN DVT1 and EINSTEIN PE2* (non-inferiority studies)Treatment period of 3, 6 or 12 months
20 mg od
N=4,845
Rivaroxaban
R
1. The EINSTEIN Investigators. N Engl J Med 2010;363:2499–25102. EINSTEIN PE. Available at: http://clinicaltrials.gov. Trial ID: NCT00439777. Accessed August 2011
30-d
ay o
bser
vatio
n af
ter
trea
tmen
t ces
satio
n
Confirmed symptomatic DVT or PE completing 6 or 12 months
of rivaroxaban or VKA
Rivaroxaban 20 mg od
PlaceboDay 1
N=1,197
EINSTEIN Extension1 (superiority study)Treatment period of 6 or 12 months
R
30-d
ay o
bser
vatio
n af
ter
trea
tmen
t ces
satio
n
*EINSTEIN PE is still ongoing
Dabigatran: RE-COVER study designs
• Primary efficacy outcome:1,2 composite of symptomatic recurrent VTE and VTE related death within 6 months
• Principal safety outcome:1,2 bleeding events
Predefined treatment period of 6 months
N=2,564
Parenteralanticoagulant
Day 1 Day 6
VKA target INR 2.5 (INR range 2.0–3.0)EstimatedN=2,589
Dabigatran etexilate 150 mg bid
R
Symptomatic VTE
RE-COVER1
Symptomatic VTE
RE-COVER II2
1. Schulman S et al. N Engl J Med 2009;361:2580-2589; 2. RE-COVER II. Available at: http://clinicaltrials.gov. Trial ID: NCT00680186. Accessed August 2011
Dabigatran: RE-MEDY
• Primary efficacy outcome: composite of recurrent symptomatic VTE (DVT and PE) and deaths related to VTE
• Secondary outcome: composite of recurrent symptomatic VTE and all-cause mortality
N=2,867
VKA target INR 2.5 (range 2.0–3.0) plus dabigatran placebo bid
Dabigatran etexilate 150 mg bid plus warfarin placebo as decided by sham INR measurementsLong-term
treatment of symptomatic
VTE (after 3–6 months’
anticoagulation)
RStandard care
Dabigatran
Day 1
Treatment period of up to 36 months
RE-MEDY. Available at: http://clinicaltrials.gov. Trial ID: NCT00329238. Accessed August 2011
Edoxaban: Hokusai-VTE study
• Primary efficacy outcome: recurrent symptomatic VTE (DVT, non-fatal and fatal PE) 12 months from randomization
• Primary safety outcome: clinically relevant bleeding (major or non-major clinically relevant bleeding) during treatment
LMWH/UFH followed by edoxaban 60 mg od for up to 12 months
LMWH/UFH and warfarin (INR 2.0–3.0) for up to 12 months
Day 1
Standard careSymptomatic DVT and/or PE VTE
R
Maximum treatment period of 12 months
Edoxaban
EstimatedN=7,500
Hokusai-VTE. Available at: http://clinicaltrials.gov. Trial ID: NCT00986154. Accessed August 2011
Thrombolytic therapy
• Consider catheter-directed thrombolytic therapy for patients with symptomatic iliofemoral DVT who have:– symptoms of less than 14 days’ duration and– good functional status and– a life expectancy of 1 year or more and– a low risk of bleeding.
Created 6/8/2017 Dr. Matthew Fay: Westcliffe Medical Group
Advice to patients
• Walk regularly after discharge from hospital.• Elevate the affected leg when sitting.• Refrain from extended travel, or travel by
aeroplane, for at least 2 weeks after starting anticoagulant treatment.
Based on the CKS topic DVT (April 2013) and NICE guidance (2012a); Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing.
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